Chemokines are a family of small, structurally related proteins that bind to seven transmembrane spanning G protein-coupled receptors. Chemokines and their receptors have an essential role in organogenesis and lymphocyte trafficking, in both homeostatic and inflammatory conditions. There is a strong association between aberrant tumour cell expression of chemokine receptors such as CXCR4 or CCR7 and cancer progression, organ-selective metastasis, and poor prognosis. Human chemokine receptor CCR9 (accession number U45982 of the GENBANK® biosequence database) was identified by Zaballos et al. (1999, J Immunol 162:5671-5; EMBL database accession number AJ132337) and Youn et al. (1999, Blood 94:2533-6). Although there are not many data for CCR9, its expression on tumour cells correlates with metastasis in the small intestine (Letsch et al., 2004, J Invest Dermatol 122:685-90; Richmond A, 2008, Clin Cancer Res 14:621-3; Amersi et al., 2008, Clin Cancer Res 14:638-45).
CCR9 is expressed almost exclusively in lymphoid cells in the thymus, infiltrating cells in small bowel, a small subset of circulating memory T lymphocytes (CCR9+α4β7hi), IgA-secreting plasma cells and plasmacytoid dendritic cells. The only known CCR9 ligand is the chemokine TECK (CCL25), which is secreted by epithelial and dendritic cells from the thymus and the small intestinal crypt epithelium. The CCR9-CCL25 interaction is a key regulator of thymocyte migration in thymus and of cell homing to the intestinal tract. Aberrant CCR9 expression in ovarian carcinomas, prostate cancer, breast cancer and melanomas is correlated with in vitro invasiveness in response to CCL25. CCR9 overexpression in acute and chronic T cell lineage leukaemia is linked to disease aggressiveness. CCR9 provides competitive advantages to tumour cells; CCL25 engagement enhances cell survival and resistance to apoptosis via the phosphatidylinositide 3-kinase (PI3K)/Akt pathway in breast and ovarian carcinomas, activates the JNK1 anti-apoptotic pathway, and enhances proliferation by activating Notch1 in leukaemia cells.
Specific therapeutic tools to treat human CCR9+ tumours growing in xenogenic models are limited to the use of toxin-coupled ligands (CCL25-PE38 fusion protein) (Hu et al., 2011, Leukaemia Res 35:1254-60) or ligand-specific antibodies alone or combined with the cytotoxic agent etoposide (Sharma et al., 2010, Int J Cancer 127:2020-30). In these strategies, the CCL25-CCR9 interaction is targeted to eliminate tumour cells; although the results have been limited, they provide evidence that CCR9 is a potential target for cancer immunotherapy.
Given the lack of therapies targeted to CCR9, there is still a need in the art to provide agents recognising CCR9 specifically that are suitable for the diagnosis, prognosis and/or treatment of a disease or condition concomitant with cells expressing CCR9.